The effects of tRNA editing deficiency on hematopoietic stem cells

To test how translational control of proteome quality affects stem cell function, we examined Aarssti/sti mice that harbor a mutation in the alanyl-tRNA synthetase, which causes a tRNA editing defect that increases amino acid misincorporation errors during translation. Aarssti/sti mice exhibited reduced HSC numbers, increased HSC proliferation and significantly diminished HSC serial reconstituting activity in vivo, but did not exhibit defects within restricted progenitors. Modest accumulation of misfolded proteins partially overwhelmed the capacity of the proteasome within HSCs, which was associated with stabilization and increased abundance of c-Myc. Conditional deletion of a single copy of Myc partially rescued serial reconstitution defects in Aarssti/sti HSCs. HSCs are thus dependent on the maintenance of proteome quality and homeostasis to preserve their self-renewal activity in vivo. RNA-seq experiment to examine the effects of a tRNA editing defect on the hematopoietic stem cell transcriptome 2 samples with 3 replicates each (6 total)